Is CDK5R2 p.Pro159Leu (c.476C>T) pathogenic?

CDK5R2 p.Pro159Leu (c.476C>T) is classified Uncertain significance in CDK5R2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely benign (0.0688); Ultra-rare (popmax 0.0124%, eas).

How common is CDK5R2 p.Pro159Leu (c.476C>T) in the general population?

CDK5R2 p.Pro159Leu (c.476C>T) is ultra-rare (popmax 0.0124%, eas) (gnomAD).

What do computational predictors say about CDK5R2 p.Pro159Leu (c.476C>T)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

CDK5R2 p.Pro159Leu

c.476C>T · rs1442704952 · VCV2481851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.97, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 490 bp · p 0.0016 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% East Asian · 4/32,382 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00254%

Overall 0.000409% 5/1,222,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0124%	8,096
European (non-Finnish)	9.32e-05%	1,072,687

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDK5R2
Protein: p.Pro159Leu
Coding: c.476C>T
MANE Select: NM_003936
dbSNP: rs1442704952
Type: single nucleotide variant
Location: chr2:218960296 (GRCh38)
Gene constraint: LOEUF 0.745 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 70.01
Residue 159: the 'disordered' region

Full CDK5R2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK5R2 p.Ala122Val Uncertain significance ★ ⚠ same type
CDK5R2 p.Ala133Thr Uncertain significance ★ ⚠ same type
CDK5R2 p.Ala144Ser Uncertain significance ★ ⚠ same type
CDK5R2 p.Ala261Ser Uncertain significance ★ ⚠ same type
CDK5R2 p.Ala331Pro Uncertain significance ★ ⚠ same type
CDK5R2 p.Arg200His Uncertain significance ★ ⚠ same type
CDK5R2 p.Arg248Cys Uncertain significance ★ ⚠ same type
CDK5R2 p.Arg248His Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdk5r2-p-pro159leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown